(Project 3 - Cassis) Recent studies demonstrate a strong association between serum levels of polychlorinated biphenyls (PCBs) and an increased odds ratio for type 2 diabetes (T2D). This proposal tests the hypothesis that coplanar PCBs act at adipocyte aryl hydrocarbon receptors (AhR) to increase expression of proinflammatory cytokines, resulting in reductions in glucose uptake and the development of insulin resistance. Further, we hypothesize that the polyphenol, resveratrol, can be used to prevent and/or treat PCB-induced elevations in adipocyte proinflammatory cytokine expression and impaired glucose homeostasis during weight loss. We demonstrated that administration of coplanar PCBs to low fat fed male and female mice induces glucose and insulin intolerance associated with adipose-specific elevations in tumor necrosis factor-? (TNF-?). Remarkably, when mice were made obese from consumption of a high fat (HF) diet, effects of PCB to impair glucose homeostasis were lost when lipophilic PCBs were sequestered at higher levels within adipose tissue lipids. However, upon weight loss, PCBs impaired glucose and insulin tolerance, limiting beneficial effects of weight loss to improve glucose homeostasis. These results suggest that obesity increases body burden of PCBs, and that release of PCBs during weight loss from adipose lipids may be harmful in the context of T2D. The anti-oxidant polyphenol and putative AhR antagonist, resveratrol, abolished acute effects of PCBs to impair glucose tolerance in mice, and protected against PCB-induced reductions in insulin signaling and glucose uptake in adipocytes.
Aim 1 will define the role of adipocyte AhR in PCB-induced impairment of glucose and insulin tolerance in lean male and female mice, and in obese mice experiencing weight loss. Results from these studies will define whether the enhanced accumulation of lipophilic PCBs to adipose tissue results in adipocyte-specific impairment of glucose uptake.
Aim 2 will define the adipocyte-specific effects of resveratrol on PCB-induced impairment of glucose homeostasis in obese male and female mice exhibiting weight loss. Results from this aim will determine if resveratrol acts to protect against PCB-induced impairment of glucose uptake and insulin resistance through an adipocyte-specific mechanism, and whether this therapeutic strategy have utility in the setting of weight loss. The impact of this research is identification of mechanisms linking PCB exposures to T2D and development of a therapeutic strategy, resveratrol, to protect against harmful effects of PCBs on glucose homeostasis in lean subjects, as well as obese subjects experiencing weight loss.

Public Health Relevance

(Project 3 - Cassis) The overall impact of this research is to identify mechanisms whereby polychlorinated biphenyls (PCBs), lipophilic environmental toxins, promote the development of insulin resistance and type 2 diabetes. Moreover, our approach will identify whether the natural polyphenol, resveratrol, can be used as an interventional strategy to protect against harmful effects of PCBs on glucose homeostasis in lean subjects, and in obese subjects experiencing weight loss.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES007380-21
Application #
9459893
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
21
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526
Deng, Pan; Barney, Jazmyne; Petriello, Michael C et al. (2018) Hepatic metabolomics reveals that liver injury increases PCB 126-induced oxidative stress and metabolic dysfunction. Chemosphere 217:140-149
Preston, Joshua D; Reynolds, Leryn J; Pearson, Kevin J (2018) Developmental Origins of Health Span and Life Span: A Mini-Review. Gerontology 64:237-245
Gupta, Prachi; Thompson, Brendan L; Wahlang, Banrida et al. (2018) The environmental pollutant, polychlorinated biphenyls, and cardiovascular disease: a potential target for antioxidant nanotherapeutics. Drug Deliv Transl Res 8:740-759
Roghani, Mohammadyousef; Jacobs, Olivia P; Miller, Anthony et al. (2018) Occurrence of chlorinated volatile organic compounds (VOCs) in a sanitary sewer system: Implications for assessing vapor intrusion alternative pathways. Sci Total Environ 616-617:1149-1162
Ahmad, Irfan; Weng, Jiaying; Stromberg, A J et al. (2018) Fluorescence based detection of polychlorinated biphenyls (PCBs) in water using hydrophobic interactions. Analyst :
Petriello, Michael C; Hoffman, Jessie B; Vsevolozhskaya, Olga et al. (2018) Dioxin-like PCB 126 increases intestinal inflammation and disrupts gut microbiota and metabolic homeostasis. Environ Pollut 242:1022-1032
Petriello, Michael C; Charnigo, Richard; Sunkara, Manjula et al. (2018) Relationship between serum trimethylamine N-oxide and exposure to dioxin-like pollutants. Environ Res 162:211-218
Bertrand, Luc; Dygert, Levi; Toborek, Michal (2017) Induction of Ischemic Stroke and Ischemia-reperfusion in Mice Using the Middle Artery Occlusion Technique and Visualization of Infarct Area. J Vis Exp :
Tang, Shuo; Bhandari, Rohit; Delaney, Sean P et al. (2017) Synthesis and characterization of thermally responsive N-isopropylacrylamide hydrogels copolymerized with novel hydrophobic polyphenolic crosslinkers. Mater Today Commun 10:46-53
Perkins, Jordan T; Petriello, Michael C; Xu, Li et al. (2017) An open-sourced statistical application for identifying complex toxicological interactions of environmental pollutants. Rev Environ Health 32:23-26

Showing the most recent 10 out of 255 publications